Because the major psychiatric disorders are common disorders with complex inheritance, unless one collects large clinical samples, there are severe practical limits on investigators' ability to test hypotheses of genetic linkage or association. We have previously collected our own series of 20 bipolar manic-depressive (BP) families with 338 cell lines. We are now engaged as the Intramural collaborators in an NIMH collaborative study, which will collect more than 150 families each with BP, schizophreni (SZ), and Alzheimer's disease. Two interview instruments have been prepare for BP and SZ families: the Diagnostic Instrument for Genetic Studies (DIGS), and the Family Interview for Genetic Studies (FIGS). A reliability study has been submitted for publication. Collection of our Branch's pedigree series for this study has begun with 4 families collected. We are also collecting bipolar pedigrees from the Sephardic Jewish population in Israel, and American families with panic disorder (19 families) and with SZ. Molecular scanning of candidate genes in unrelated ill patients, and demonstration of more variants in patients than controls, is a powerful alternative strategy to linkage. We now have collected 86 unrelated probands with SZ and 44 with BP for these studies. A course on systematic diagnosis and interviewing was given for the fifth time this year. This project also includes a prospective study of adolescent and young adult children at high risk for affective disorder by virtue of the fact that they are offspring of bipolar parents.